The Great Heart Failure Mystery

This post is best viewed from the blog website: http://siriasis.blogspot.com/


Motivation: One of the "bread and butter" diagnoses in inpatient medicine is systolic heart failure exacerbation - we all see it, we all treat it, but do we understand it?  I first wondered about this question last year during my basic medicine clerkship.  The etiology of systolic heart failure  is usually answered with some notion of overstretching the heart.  For me, the difficulty was that it is easy to see how overstretching a single muscle fiber can lead to weakness, but do we really overstretch an entire organ - especially an already dilated organ (like the enlarged heart in dilated cardiomyopathy)?

The traditional teaching and general consensus for decompensated systolic heart failure is that with volume overload, pre-load exceeds the capacity of the Frank-Starling compensation and then an inverse relation holds with increased filling resulting in decreased cardiac output.  The presumed basis is that there may be lack of productive overlap of muscle fibers with increased filling.  But, is there solid empirical data for this explanation?

The answer is shockingly no.  I have even asked cardiologists to confirm this assessment.  Of course, lack of data does not imply that the traditional teaching is false.  So, are there physiological studies about the response of the dilated heart to filling?

Paper: Evidence of the Frank-Starling Mechanism in the Failing Human Heart.  Holubarsch, C., et. al. Circulation (1996); 94: 683-689. http://circ.ahajournals.org/cgi/content/full/94/4/683

Method: Five human hearts with end-stage dilated cardiomyopathy were excised from patients receiving heart transplants.  The average ejection fraction of these hearts was 17%.  These hearts were kept alive artificially (really cool!)  using oxygenated blood.  Pressure and volume relationships were directly measured.  The hearts were paced using epicardial leads.  For controls, two healthy hearts were used which were originally destined for transplantation but could not be transplanted due to technical reasons.

Results:
For this experiment, I think that pictures tell more than any description.  So, I will paste some of the key graphs and point out the pertinent results:

In the graph on the left, the x-axis describes the volume of the left ventricle.  In Figure A, as the volume increases, the pressure inside the ventricle increases.




In B, we see that as the volume increases the diastolic pressure increases and the generated systolic pressure increases as well (the Frank Starling mechanism).  For perspective, the hearts here are really being filled up - the average diastolic volume is about 120 mL.





C.  Observe in this figure that as the LV is being filled up, the net generated pressure (which is simply systolic pressure minus diastolic pressure) decreases despite an intact Frank-Starling mechanism (the diastolic pressure increases at a faster rate than the systolic pressure at high volumes).

In the figure on the right, to investigate the state of Frank-Starling effect on muscle strips rather than whole organ, individual muscle strips were isolated from healthy hearts (top curve) and from failing hearts (bottom curve).  The total tension generated was measured in response to different muscle lengths.  As seen, the healthy heart was able to generate a lot more force in response to increased stretch.  But, while the response of the failing heart was more moderate, there is no evidence of "falling-off" the Starling curve.






Conclusion: This paper does not conclusively answer the physiologic basis of dilated cardiomyopathy but sheds some light on couple of areas.  (1) Even in failing hearts with weak contractility, the Frank-Starling effect is likely preserved even when stretched out by volume overload.  (2) Besides preload, cardiac contractility is controlled by two other factors: heart rate (increased contractility at increased heart rates) and neurohumoral responses (such as to catecholamines).  It may be possible that increased volume somehow upsets the responses to the latter two mechanisms rather than disrupting the Frank-Startling mechanism.  Anyway, there is a story yet to be told ....

Cell Phone and Brain Cancer

Motivation: Yesterday, I was talking on my new smartphone, and my ear grew warm.  The warmth spurred thoughts about a number of recent Google News posts warning about the dangers of cell phone use.  Do cell phones cause brain cancer?

Paper: Meta-analysis of long-term mobile phone use and the association with brain tumours.  Hardell, L. et al. Int. J. of Onc. (2008) 32: 1097-1103.

Method: Review of prospective and case-control studies that studied association of intracranial neoplasms and cell phone usage.

Results:
Glioma: In the meta-analysis using six case-control studies, the odds ratio of developing a glioma in the ipsilateral side to cell phone usage was 2.0 (CI: 1.2-3.4).  The odds ratio in the contralateral side was 1.1 (CI: 0.6-2.0).  The largest included study was a multi-national case-control study that studied cell-phone users, who had used cell phones for greater than ten years.  In the study, there were 77 cases of gliomas and 117 controls.  The odds ratio for gliomas in the side ipsilateral to cell phone use was 1.4 (CI: 1.01-1.9).  The OR for gliomas in the contralateral side was 1.0 (CI: 0.7-1.4).

Acoustic Neuroma: Nine case-control studies have examined this issue.  The meta-analysis yielded an odds ratio of 0.9 (CI: 0.7-1.1).  Of the nine studies, eight had not found any association.  When examining only the three studies looking at cell-phone users who had used cell phones for greater than 10 years, the odds ratio for acoustic neuroma in the ipsilateral side to use was 2.4 (CI: 1.1-5.3) and contralateral side was 1.2 (CI: 0.7-2.2).  Two of the three studies included in this analysis reached statistical significance for ipsilateral acoustic neuroma.

Meningioma: There were seven case-control studies studying this issue.  The meta-analysis gave an odds-ratio of 0.8 (CI: 0.7-0.99).  In the four case-control studies examining more than 10 year cell-phone users, the odds ratio for meningioma in the ipsilateral side was 1.7 (CI: 0.99-3.1) and in the contralateral side was 1.0 (CI: 0.3-3.1).  None of the four case-control studies reached statistical significance.

Conclusion: The association between cell-phone use and neoplasms is obviously of great public concern given the exploding number of global users.  The meta-analysis primarily found that cell-phone users of more than ten years had a greater likelihood of developing gliomas and acoustic neuromas in the side ipsilateral to cell phone use.  The study passes common sense tests because there appears to be greater association with length of use and site of use.  On the other hand, there are a couple of caveats.  The first is that this meta-analysis primarily consisted of case-control studies which are weak in proving causality.  People who use cell-phones, for instance, are also more likely to use other gadgets which emit radio-frequency or live in cities, where citizens may also be exposed to other toxins.  The second caveat is that gliomas are as such infrequent events, an odds-ratio of 2.0 may be scary but may not be very clinically significant (two times the odds of a rare event is not that frequent).  On the flip side, if the risk of neoplasm is dose dependent, the rates of neoplasms after multiple years may be significantly high.  For now, given our uncertain knowledge, I am buying a Bluetooth headset and getting a holster to separate the cell-phone from body contact!

Case study

When I was on Polk, I had a patient with a CD4<200 who presented with HA x 1wk. She didn't appear toxic and described the headache as more of an annoyance than anything else. Her basic labs were normal, and she was afebrile. Having a low threshold in such a patient, we did an LP which was only remarkable for a minimally elevated protein and no organisms on gram stain. Lacking much to go on, I was about to attribute her symptoms to a tension headache. However, the next morning, I was talking to her and randomly looked down at her hands (image below is from the actual patient, courtesy of the Department of Photo Path at JHH). Look familiar? I sent an RPR & VDRL which were positive--both serum and CSF. Neurosyphilis with a palmar rash! She had a PICC line placed for a 14 day course of IV PCN G. Verging on corny, this case gave me a renewed appreciation for the physical exam.

Home remedies

Fantastic posts, Shamik!! So, I saw a case of "neutrophilic urticaria" today in derm clinic. Obviously, most urticaria is hypersensitivity IgE mediated, but this is a more rare and treatment-resistant form of urticaria. It's typically treated with dapsone, which actually inhibits neutrophil chemotaxis. This patient, however, was G6PD deficient and had severe hemolysis with dapsone and, furthermore, developed methemoglobinemia. It got me to thinking though. What else inhibits neutrophil function and could potentially be used as an alternative treatment? I did a pubmed search and found the following article published in CHEST (2000) by Rennard et al, which I thought was interesting/entertaining:

"Chicken soup inhibits neutrophil chemotaxis in vitro."
ABSTRACT: Chicken soup has long been regarded as a remedy for symptomatic upper respiratory tract infections. As it is likely that the clinical similarity of the diverse infectious processes that can result in "colds" is due to a shared inflammatory response, an effect of chicken soup in mitigating inflammation could account for its attested benefits. To evaluate this, a traditional chicken soup was tested for its ability to inhibit neutrophil migration using the standard Boyden blindwell chemotaxis chamber assay with zymosan-activated serum and fMet-Leu-Phe as chemoattractants. Chicken soup significantly inhibited neutrophil migration and did so in a concentration-dependent manner. The activity was present in a nonparticulate component of the chicken soup. All of the vegetables present in the soup and the chicken individually had inhibitory activity, although only the chicken lacked cytotoxic activity. Interestingly, the complete soup also lacked cytotoxic activity. Commercial soups varied greatly in their inhibitory activity. The present study, therefore, suggests that chicken soup may contain a number of substances with beneficial medicinal activity. A mild anti-inflammatory effect could be one mechanism by which the soup could result in the mitigation of symptomatic upper respiratory tract infections.

This seemed to be a pretty rigorous study of chicken soup published in Chest, of all journals! I continued to wonder: "Well, what about orange juice?" I found a Cochrane review article, "Vitamin C for preventing and treating the common cold." by Douglas et al (2004). The trials in which vitamin C was introduced at the onset of colds as therapy did not show any benefit in doses up to 4 grams daily, but one large trial reported equivocal benefit from an 8 gram therapeutic dose at onset of symptoms. Now, you may ask yourself, "How many glasses of OJ would it take to get 8g of vitamin C." And, yes, I did the calculation. It would take 64.5 8oz glasses of orange juice to get an "equivocal benefit."

In brief, no, OJ doesn't help, and who knows if chicken soup has any clinical benefit...but it inhibits neutrophil chemotaxis which is pretty cool. So, now you have the answer next time someone asks you about OJ and chicken soup!

CPR-Why not?

Motivation: When I was in eighth grade, I was traveling through the Detroit Airport and saw a man ten feet from me collapse.  He just folded senseless to the ground without any preliminaries and stayed that way.  My first response was to blink my eyes to assure myself that this was real.  The unreal feeling was succeeded by an enveloping numbness.  I did nothing and gazed dumbly at the man on the ground.  Of course, if everyone had acted as I did, the man would not have received any help.  His wife cried out, and someone else must have done something (I was not noticing much).  Soon, EMS came and cleared us out.  Interestingly, nobody did CPR.

Recently, as I learned in my ED clerkship orientation, the American Heart Association reformulated the CPR guidelines to eliminate rescue breathing from the CPR algorithm for the lay person.  Although many factors went into this decision including emerging evidence that in the first few minutes chest compressions are more important than breaths, one of the key cited reasons is that removing rescue breathing may encourage more people to do CPR, which substantially increases chances of survival.  Only 20-30% of out-of-hospital cardiac arrests ever receive CPR.  I wondered, however, if people don't do CPR because they are afraid of rescue breathing or or because they are scared out of their minds - like me.  Here is an article examining this very question:

Article: CPR Training and CPR Performance: Do CPR-trained Bystanders Perform CPR?  Swor, R., et. al. Acad. Emerg. Med. 2006 (13): 596-601.  http://www.ncbi.nlm.nih.gov/pubmed/16614455?dopt=Abstract

Method: A prospective multicentered study in Southeastern Michigan in which individuals calling 911 for cardiopulmonary arrest between 1997-2003 were followed-up and interviewed.  Arrests occurring in nursing home facilities were not counted.

Results: In the study period, 868 subjects suffered arrest for whom 911 calls were made.  Of these 868 calls, 684 callers were followed-up and interviewed (78.8%).  Of the missing callers, 163 (18.8%) could not be identified or contacted while 21 refused to give permission (2.4%).  Callers were most frequently family member of the victim (69.6%).

Patient population: The patient population was predominantly male (68%) and suffered an arrest in a residential setting (80.8%).  About 17% survived to hospital admission, but only 6.6% survived to hospital discharge!

Responder characteristics: Among bystanders, 54% had received CPR training during their lifetime.  In all, CPR was started before EMS arrival in 33.6% of cases.  For bystanders, factors positively associated with starting CPR were younger age (less than 50), public location, witnessed arrest, and higher educational level. Among those who were CPR trained, only 35.1% initiated CPR.  Factors positively associated in this subgroup included public location, witnessed arrest, higher education level, and recent CPR training.  Younger age was not correlated in this population.

Reason for not doing CPR:  For those who were CPR trained, the most common causes recalled for not initiating CPR were panic (38.7%), concern about performing CPR correctly (10.8%), physical inability to do CPR (3.6%), and thoughts about potentially harming the patient (1.8%).  A significant fraction (4.3%) did not perform CPR because they thought the patient was dead.  Only four callers (1.4%) identified mouth-to-mouth resuscitation as a barrier.  None identified concern about infectious diseases.

Conclusion: This study proved once again that while arrest outside hospital has poor prognosis, many potential lives are being lost because CPR is not initiated soon enough.  What I found fascinating in this study was that even among the CPR trained, only 35% initiated CPR.  Overwhelmingly, the most common reason for not doing CPR was panic and not aversion to mouth-to-mouth resuscitation or concern about infectious diseases as commonly thought.  One point to keep in mind is that the whole study of bystanders is susceptible to the psychological bias that those not performing CPR may not want to disclose their true reasons from shame.  I also found the association between public location and bystander initiation of CPR interesting.  One reason may be that presence of more people decreases panic and incites action.

Given the high panic and anxiety surrounding such cases, I think that simplifying the CPR regimen is probably a very good thing.  If I know that when someone goes down before me I just have to kneel down and pump at 100 compressions a minute, I may be more likely to do it.  Hopefully, there will be widespread dissemination of this knowledge through posters and other public education tools.

Dabigatran - Goodbye to coumadin?

Motivation: After even a few months in the wards, I think that all of us learn that coumadin/warfarin inspires mixed emotions.  With too little drug, you don't get the proven benefits.  And, with too much, there is chance of bleeding - even to death.  This summer, while in the neuro service, I saw a man on coumadin die from intraventricular hemorrhage.  The problem with coumadin is that its metabolism is affected by so many environmental variables that steady anti-coagulation is hard to maintain.  Recently, the FDA approved dabigatran, which is a direct inhibitor of thrombin, for anti-coagulation in atrial fibrillation.  It is expected that in the future, dabigatran can be substituted for most cases of anticoagulation.   But, what is the data to justify replacing good old coumadin?

Paper(s): Two primary studies for dabigatran: (1) Trial RE-COVER: Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. Schulman, S. et. al. NEJM, 2009 (361): 2342-2352.  (2) Trial RE-LY: Dabigatran versus Warfarin in Patients with Atrial Fibrillation. Stuart, J. et. al. NEJM, 2009 (361): 1139-1151.

Links: RE-COVER: http://www.nejm.org/doi/full/10.1056/NEJMoa0906598#t=article; RE-LY: http://www.nejm.org/doi/full/10.1056/NEJMoa0905561#t=article

Methods: For the RE-COVER study, 2,539 patients were recruited from 228 clinical centers in 29 countries and, in a blinded way, randomized to a fixed dose of dabigatran (150 mg bid) or warfarin adjusted to INR of 2.0-3.0.  Patients were essentially adults with symptomatic deep vein thrombosis who did not have pulmonary embolism with hemodynamic instability.  The primary end-point was symptomatic venous thromboembolism (VTE) or death from VTE.  For the RE-LY study, 18,113 patients were recruited from 951 clinical centers in 44 countries and randomized to a fixed dose of dabigatran (110 mg bid or 150 mg bid) or warfarin adjusted to INR of 2.0-3.0.  In the study, patients essentially had to have atrial fibrillation plus one more condition: previous stroke/TIA, heart failure, or older age (65-74) with diabetes, HTN, or CAD.  The primary end-point was stroke or systemic embolism.

Results:
RE-COVER:  In the primary end-point of symptomatic or deadly VTE, 2.4% in the dabigatran group had such events while 2.1% in the warfarin group (difference not significant).  There was no difference in overall mortality.  In the warfarin group, INR was therapeutic for only 66% of the time. In terms of safety, there were equivalent rates for any bleeding events or for major bleeds (1.6% in dabigatran vs. 1.9% in coumadin).  Patients in dabigatran were marginally more likely to experience any adverse event (9.0% vs. 6.8%, p=0.05).  Follow-up was for six months and essentially complete (>98%).

RE-LY: For the primary end-point of stroke or systemic embolism, the 150 mg dose of dabigatran was superior to coumadin (rate of 1.11% vs. 1.69% per year, p<0.001).  The 110 mg dose of dabigatran was equivalent to coumadin (rate of stroke or embolism: 1.53% vs. 1.69%, p=0.34).  Rates of hemorrhagic stroke were lower in the 150 mg group compared to warfarin (0.10% vs. 0.38%, p<0.001).  Similar trend was found in the 110 mg group.  Overall rates of mortality were not significantly different though there was a slight trend of lower mortality in the 150 mg group (3.64% vs. 4.13%, p=0.051).

Follow-up was essentially complete in all patients for two years.  In the warfarin group, INR was therapeutic only 64% of the time.  In terms of safety, rate of MI was higher in the 150 mg group compared to warfarin (0.74% vs. 0.53%, p = 0.048).  Same trend held for 110 mg group.  Overall, life-threatening bleeds were lower in both dabigatran group compared to warfarin, but rates of major GI bleeds were higher in the 150 mg dabigatran group compared to warfarin (1.51% vs. 1.02%, p<0.001).  In the 110 mg group, rates of GI bleeding were comparable.

Conclusion: Overall, both studies were well done with good follow-up and clinically relevant end-points chosen.  The RE-COVER trial satisfactorily showed, I think, that dabigatran was equivalent to warfarin in terms of preventing complications of thromboembolism.  Another interesting result from this trial was that even though warfarin was not therapeutic 1/3 of the time in the trial, the missed target did not seem to make any difference for thromboembolic events or bleeding events when compared with dabigatran, which presumably has pretty constant anti-coagulation all of the time.  The RE-LY also provided many interesting results.  On one hand, 150 mg dose of dabigatran proved to be superior to coumadin (and 110 mg dose) for preventing embolic events from atrial-fibrillation.  On the other hand, the side-effect of dabigatran is a mixed bag.  While it has lower rates of potentially deadly intraventricular hemorrhage and life-threatening bleeds, dabigatran had higher rates of MI and GI bleeds - not altogether benign either.  There is no good explanation for why dabigatran has higher rates of MI.  Finally, dabigatran is estimated to cost about five times more than coumadin.  What this does for our health care spending with 30 million prescriptions for warfarin each year is an open issue.  In conclusion, I think dabigatran is a definite first choice for patients with atrial-fibrillation or DVT with poor follow-up in INR clinics and good first-choice alternative in other patients with atrial fibrillation, who can afford the drug and understand the varying side-effect profile.

Giving an infant candy - does it work?

Motivation: In pediatrics clerkship, I have come across babies who just howl after blood draws, and one of the techniques we use is coating their pacifier with a sweet liquid.  I guess the theory is that sugar makes babies happy and must therefore counteract the pain.  But, does the sugar work?  Or, should we provide babies with analgesics instead?

Turns out that this topic has been extensively studied in newborns (with 44 RCTs!) stemming from concerns about initial pain experience on subsequent neurodevelopment, and based on subjective behavioral changes, sugar pacifies babies.  But, recent evidence suggests that neonates are perhaps too immature to link pain experience and behavior reliably.  So, does sugar really help?

Paper: Oral Sucrose as an Analgesic Drug for Procedural Pain in Newborn Infants: A Randomised Controlled Trial.  Slater, R., Cornellisen, L., et. al. Lancet, 2010 (376): 1225-1232.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61303-7/abstract?rss=yes#

Method: At the University College Hospital in London, 59 full-term healthy neonates were randomized to either 0.5 mL 24% sucrose solution or 0.5  mL sterile water before receiving a heel-stick.  Before the babies received the heel-stick, they were subjected to a control non-painful stimulus by just touching the blunt end of the lancet to their heels.  The cortical response to both the control and noxious stimuli was recorded via an EEG.  The primary outcome was difference in pain-specific EEG activity in response to treatment with sugar.  Secondary outcomes were observation of facial expression and physiological changes.  Both parents and clinicians were entirely blinded to the identity of the administered solution.

Results: Because of technical difficulties of performing EEG on squirming babies and other measurement barriers, the sucrose group ultimately had 20 neonates and the control group had 24 neonates.  The two groups were not substantially different in baseline characteristics after the dropout.

There was no difference in cortical pain-specific EEG changes between the sucrose group and control group. Physiologically, there were no differences in heart rate or oxygen saturation.  However, based on facial expression, babies who received sucrose were less likely to alter facial expression to pain (35% in the sucrose group did not show any facial changes to heel-stick while all babies in the control group had facial changes like crying).

Conclusion: After this study, my conclusion is that we really don't know what babies are feeling.  The key fact that we want to understand is the subjective experience of pain in babies.  Since neonates do not talk, there is no definite gold standard.  Previously, the facial expression was used as a measure of the subjective experience.  This paper challenges that viewpoint.  There are two alternative explanations for the paper's results.  One is that the EEG is simply measuring nonciceptive input to the brain, and the facial expression is showing how the baby is processing that input.  From this perspective, relying on the baby's facial expression makes more sense.  Alternatively, the sucrose may be reflexively changing the baby's facial expression, but the pain is felt in equal intensity in the cortex.  From this viewpoint, relying on the EEG cortical response makes more sense.  Right now, I think that the only way to separate these alternative explanations is to do longer term studies to see which pain response is more closely linked with aberrant neurodevelopment.